Hcv inhibitors

Abstract

The present invention relates to compounds that are useful in the treatment of viruses belonging to Flaviviridae, including flaviviruses, pestiviruses, and hepaciviruses. The invention includes compounds useful for the treatment or prophylaxis of dengue fever, yellow fever, West Nile virus, and HCV.

1 . A method for the treatment or prophylaxis of Flaviviridae viruses through administration of a compound of formula (I): 
     
       
         
         
             
             
         
       
       wherein 
       n is 0, 1, or 2; 
       X is NH, O, or S(O) m ; 
       each R is the same or different and is independently selected from the group consisting
 of halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R 10 cycloalkyl, Ay, —NHR 10 Ay, Het, —NHHet, —NHR 10 Het, —OR 2 , —OAy, —OHet, —R 10 OR 2 , —NR 2 R 3 , —NR 2 Ay, —R 10 NR 2 R 3 , —R 10 NR 2 Ay, —R 10 C(O)R 2 , —C(O)R 2 , —CO 2 R 2 , —R 10 CO 2 R 2 , —C(O)NR 2 R 3 , —C(O)Ay, —C(O)NR 2 Ay, —C(O)Het, —C(O)NHR 10 Het, —R 10 C(O)NR 2 R 3 , —C(S)NR 2 R 3 , —R 10 C(S)NR 2 R 3 , —R 10 NHC(NH)NR 2 R 3 , —C(NH)NR 2 R 3 , —R 10 C(NH)NR 2 R 3 , —S(O) 2 NR 2 R 3 , —S(O) 2 NR 2 Ay, —R 10 SO 2 NHCOR 2 , —R 10 SO 2 NR 2 R 3 , —R 10 SO 2 R 2 , —S(O) m R 2 , cyano, nitro, or azido; 
 
       each R 1  is the same or different and is independently selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R 10  cycloalkyl, Ay, —NHR 10 Ay, Het, —NHHet, —NHR 10 Het, —OR 2 , —OAy, —OHet, —R 10 OR 2 , —NR 2 R 3 , —NR 2 Ay, —R 10 NR 2 R 3 , —R 10 NR 2 Ay, —R 10 C(O)R 2 , —C(O)R 2 ,
 —CO 2 R 2 , —R 10 CO 2 R 2 , —C(O)NR 2 R 3 , —C(O)Ay, —C(O)NR 2 Ay, —C(O)Het, —C(O)NHR 10 Het, —R 10 C(O)NR 2 R 3 , —C(S)NR 2 R 3 , —R 10 C(S)NR 2 R 3 , —R 10 NHC(NH)NR 2 R 3 , —C(NH)NR 2 R 3 , —R 10 C(NH)NR 2 R 3 , —S(O) 2 NR 2 R 3 , —S(O) 2 NR 2 Ay, —R 10 SO 2 NHCOR 2 , —R 10 SO 2 NR 2 R 3 , —R 10 SO 2 R 2 , —S(O) m R 2 , cyano, nitro, or azido; 
 
       each m independently is 0, 1, or 2; 
       each R 10  is the same or different and is independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene, and alkynylene; 
       p and q are each independently selected from 0, 1, 2, 3, 4, or 5; 
       each of R 2  and R 3  are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R 10 cycloalkyl, —R 10 OH, —R 10 (OR 10 ) w , and —R 10 NR 4 R 5 ; 
       w is 1-10; 
       each of R 4  and R 5  are the same or different and are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; 
       Ay represents an aryl group; 
       Het represents a 5- or 6-membered heterocyclyl or heteroaryl group; 
       ring A is aryl or heteroaryl; and 
       pharmaceutically acceptable salts and solvates. 
     
   
   
       2 . The method of  claim 1  wherein the virus is a flaviviruses, a pestiviruses, or a hepaciviruses. 
   
   
       3 . The method of  claim 2  wherein the virus is associated with a human disease selected from dengue fever, yellow fever, west nile virus, and HCV. 
   
   
       4 . The method of  claim 3  wherein the human disease is HCV infection. 
   
   
       5 . The method of  claim 1  wherein X is NH. 
   
   
       6 . The compound of  claim 1  wherein alkyl is C 1 -C 6  alkyl, alkoxy is C 1 -C 6  alkoxy, and haloalkyl is C 1 -C 6  haloalkyl. 
   
   
       7 . The method of  claim 1  wherein at least p or q is not 0. 
   
   
       8 . The method of  claim 1  wherein both p and q are each 1. 
   
   
       9 . The method of  claim 1  wherein n is 1 or 2. 
   
   
       10 . The method of  claim 9  wherein n is 1. 
   
   
       11 . The method of  claim 1  wherein R is selected from halogen, alkyl, haloalkyl, cycloalkyl, —R 10 cycloalkyl, Ay, Het, —OR 2 , —R 10 OR 2 , —NR 2 R 3 , —COR 2 , —CO 2 R 2 , —CONR 2 R 3 , —S(O) 2 NR 2 R 3 , cyano, nitro, or azido. 
   
   
       12 . The method of  claim 11  wherein R is selected from halogen, alkyl, haloalkyl, cycloalkyl, —R 10 cycloalkyl, Ay, Het, —OR 2 , —R 10 OR 2 , —NR 2 R 3 , —COR 2 , —CONR 2 R 3 , —S(O) 2 NR 2 R 3 , or cyano. 
   
   
       13 . The method of  claim 12  wherein R is selected from halogen, alkyl, or haloalkyl. 
   
   
       14 . The method of  claim 13  wherein R is selected from Cl or Br. 
   
   
       15 . The method of  claim 13  wherein R is substituted para to the depicted N atom. 
   
   
       16 . The method of  claim 1  wherein R 1  selected from halogen, alkyl, haloalkyl, Ay, Het, —OR 2 , —R 10 OR 2 , —NR 2 R 3 , —COR 2 , —CO 2 R 2 , —CONR 2 R 3 , —S(O) 2 NR 2 R 3 , —S(O) m R 2 , cyano, nitro, or azido. 
   
   
       17 . The method of  claim 16  wherein R 1  is selected from halogen, alkyl, haloalkyl, —OR 2 , cyano, or nitro. 
   
   
       18 . The method of  claim 17  wherein R 1  is selected from halogen, alkyl, haloalkyl, —OR 2 . 
   
   
       19 . The method of  claim 18  wherein q is 1 or 2. 
   
   
       20 . The method of  claim 1  wherein the A ring is aryl. 
   
   
       21 . The method of  claim 20  wherein the A ring is phenyl. 
   
   
       22 . The method of  claim 1  wherein the A ring is heteroaryl. 
   
   
       23 . The method of  claim 22  wherein the heteroaryl is pyrimidinyl, pyridyl, or benzothiazolyl. 
   
   
       24 . The method of  claim 23  wherein the heteroaryl is pyrimidinyl or pyridyl. 
   
   
       25 . The method of  claim 24  wherein q is 0, 1, or 2. 
   
   
       26 . The method of  claim 1  wherein when p is not 0, then each R is the same or different and is independently selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R 10 cycloalkyl, Ay, —NHR 10 Ay, Het, —NHHet, —NHR 10 Het, —R 10 OR 2 , —NR 2 R 3 , —NR 2 Ay, —R 10 NR 2 R 3 , —R 10 NR 2 Ay, —R 10 C(O)R 2 , —C(O)R 2 , —CO 2 R 2 , —R 10 CO 2 R 2 , —C(O)NR 2 R 3 , —C(O)Ay, —C(O)NR 2 Ay, —C(O)Het, —C(O)NHR 10 Het, —R 10 C(O)NR 2 R 3 , —C(S)NR 2 R 3 , —R 10 C(S)NR 2 R 3 , —R 10 NHC(NH)NR 2 R 3 , —C(NH)NR 2 R 3 , —R 10 C(NH)NR 2 R 3 , —S(O) 2 NR 2 R 3 , —S(O) 2 NR 2 Ay, —R 10 SO 2 NHCOR 2 , —R 10 SO 2 NR 2 R 3 , —R 10 SO 2 R 2 , —S(O) m R 2 , cyano, nitro, or azido. 
   
   
       27 . A use of a compound of formula (I): 
     
       
         
         
             
             
         
       
       wherein: 
       n is 0, 1, or 2; 
       X is NH, O, or S(O) m ; 
       each R is the same or different and is independently selected from the group consisting
 of halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R 10 cycloalkyl, Ay, —NHR 10 Ay, Het, —NHHet, —NHR 10 Het, —OR 2 , —OAy, —OHet, —R 10 OR 2 , —NR 2 R 3 , —NR 2 Ay, —R 10 NR 2 R 3 , —R 10 NR 2 Ay, —R 10 C(O)R 2 , —C(O)R 2 , —CO 2 R 2 , —R 10 CO 2 R 2 , —C(O)NR 2 R 3 , —C(O)Ay, —C(O)NR 2 Ay, —C(O)Het, —C(O)NHR 10 Het, —R 10 C(O)NR 2 R 3 , —C(S)NR 2 R 3 , —R 10 C(S)NR 2 R 3 , —R 10 NHC(NH)NR 2 R 3 , —C(NH)NR 2 R 3 , —R 10 C(NH)NR 2 R 3 , —S(O) 2 NR 2 R 3 , —S(O) 2 NR 2 Ay, —R 10 SO 2 NHCOR 2 , —R 10 SO 2 NR 2 R 3 , —R 10 SO 2 R 2 , —S(O) m R 2 , cyano, nitro, or azido; 
 
       each R 1  is the same or different and is independently selected from the group consisting of halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R 10  cycloalkyl, Ay, —NHR 10 Ay, Het, —NHHet, —NHR 10 Het, —OR 2 , —OAy, —OHet, —R 10 OR 2 , —NR 2 R 3 , —NR 2 Ay, —R 10 NR 2 R 3 , —R 10 NR 2 Ay, —R 10 C(O)R 2 , —C(O)R 2 , —CO 2 R 2 , —R 10 CO 2 R 2 , —C(O)NR 2 R 3 , —C(O)Ay, —C(O)NR 2 Ay, —C(O)Het, —C(O)NHR 10 Het, —R 10 C(O)NR 2 R 3 , —C(S)NR 2 R 3 , —R 10 C(S)NR 2 R 3 , —R 10 NHC(NH)NR 2 R 3 , —C(NH)NR 2 R 3 , —R 10 C(NH)NR 2 R 3 , —S(O) 2 NR 2 R 3 , —S(O) 2 NR 2 Ay, —R 10 SO 2 NHCOR 2 , —R 10 SO 2 NR 2 R 3 , —R 10 SO 2 R 2 , —S(O) m R 2 , cyano, nitro, or azido; 
       each m independently is 0, 1, or 2; 
       each R 10  is the same or different and is independently selected from alkylene, cycloalkylene, alkenylene, cycloalkenylene, and alkynylene; 
       p and q are each independently selected from 0, 1, 2, 3, 4, or 5; 
       each of R 2  and R 3  are the same or different and are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, —R 10 cycloalkyl, —R 10 OH, —R 10 (OR 10 ) w , and —R 10 NR 4 R 5 ; 
       w is 1-10; 
       each of R 4  and R 5  are the same or different and are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl; 
       Ay represents an aryl group; 
       Het represents a 5- or 6-membered heterocyclyl or heteroaryl group; 
       ring A is aryl or heteroaryl; and 
       pharmaceutically acceptable salts and solvates thereof, in the manufacture of a medicament for use in the treatment or prophylaxis of viruses belonging to Flaviviridae. 
     
   
   
       28 . The use according to  claim 27  wherein the virus is a flavivirus, a pestivirus, or a hepacivirus. 
   
   
       29 . The use according to  claim 28  wherein the virus is associated with a human disease or condition selected from dengue fever, yellow fever, west nile virus, or HCV. 
   
   
       30 . The use according to  claim 29  wherein the condition or disease is HCV.